rs1399774

Variant names:

• chr3-189868393-A-G
• rs1399774
• NM_003722.5:c.993-187A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003722.5(TP63):​c.993-187A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,196 control chromosomes in the GnomAD database, including 2,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2616 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52
• Publications: 5 publications found

Genes affected

TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

TP63 Gene-Disease associations (from GenCC):

• ADULT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• split hand-foot malformation 4

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• EEC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-189868393-A-G is Benign according to our data. Variant chr3-189868393-A-G is described in ClinVar as Benign. ClinVar VariationId is 1251400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.993-187A>G		intron_variant	Intron 7 of 13	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.711-187A>G		intron_variant	Intron 5 of 11	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.993-187A>G		intron_variant	Intron 7 of 13	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.711-187A>G		intron_variant	Intron 5 of 11	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25446 AN: 152076 Hom.: 2618 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.0995

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25437 AN: 152196 Hom.: 2616 Cov.: 32 AF XY: 0.163 AC XY: 12131 AN XY: 74412

African (AFR) AF: 0.0592 AC: 2458 AN: 41526

American (AMR) AF: 0.201 AC: 3076 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3472

East Asian (EAS) AF: 0.195 AC: 1011 AN: 5182

South Asian (SAS) AF: 0.100 AC: 483 AN: 4832

European-Finnish (FIN) AF: 0.163 AC: 1727 AN: 10586

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15526 AN: 67986

Other (OTH) AF: 0.191 AC: 403 AN: 2108

Alfa AF: 0.213 Hom.: 1885

Bravo AF: 0.168

Asia WGS AF: 0.129 AC: 454 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.60
PhyloP100		1.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1399774; hg19: chr3-189586182; COSMIC: COSV53213230; COSMIC: COSV53213230;